PEG-PLA used in development of nanoparticle delivered SiRNA based cancer immunotherapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including PEG-PLA. One of the more insidious facets of cancer is its ability to either disarm or bypass the human immune system. An attractive chemotherapeutic target is to disable this ability so that the human immune system attacks cancer cells the same way it would attack an infection. Such a technique has advantages over conventional anti-proliferative chemotherapeutic agents (such as paclitaxel) as it is specific in its activity against cancer cells. Recently PEG-PLA block polymer was used by researchers to deliver siRNA to T-cells rendering them active against cancer cells. This research holds promise to develop a ‘cancer vaccine’ so that the body’s immune system can fight the cancer off with much greater safety and efficacy than conventional chemotherapy. Read more: Hosseini, Maryam, Mostafa Haji-Fatahaliha, Farhad Jadidi-Niaragh, Jafar Majidi, and Mehdi Yousefi. "The use of nanoparticles as a promising therapeutic approach in cancer immunotherapy." Artificial cells, nanomedicine, and biotechnology 44, no. 4 (2016): 1051-1061. http://www.tandfonline.com/doi/abs/10.3109/21691401.2014.998830

“Abstract: The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4+ and CD8+ T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8+ T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma. Graphical abstract: T cell mediated immunotherapy is an effective treatment option for malignant melanoma. It is critical for such immunotherapy to obtain a sufficient number of functional/activated T cells. However, CTLA-4 plays a potent inhibitory role in T cell activation and proliferation, which significantly curbs T cell-mediated tumor rejection. Hence, we investigated a method to exploit a nanoparticle delivery system to efficiently deliver siRNA (NPsiCTLA-4) targeting an immune checkpoint molecule, i.e. cytotoxic T lymphocyte-associated molecule-4, to manipulate or modulate tumor-infiltrating T cells and to assess the effects of NPsiCTLA4 on the blockade of CTLA-4 and the resulting enhancement of T cell mediated anti-tumor immunotherapy. Keywords: Cancer immunotherapy; Nanoparticle; Tumor-infiltrating T cells; Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)”